Pharmacogenomics J. 2021 Mar 17. doi: 10.1038/s41397-021-00232-w. Online ahead of print.

ABSTRACT

The demonstration of the link between certain genetic variations and drug response has allowed the emergence of pharmacogenetics, which offers many opportunities to improve patient care. Type-2 diabetes mellitus is a disease for which several gene polymorphisms have been reported to be associated with drug response. Sulfonylureas are commonly used for the management of this disease. Genetic polymorphisms of CYP2C9, the main enzyme involved in the metabolism of sulfonylureas, have been associated with the risk of severe hypoglycaemia, particularly in poor metabolizers carrying CYP2C9 *3/*3 genotype, and especially in the case of patients treated with glimepiride. The objectives of the present study were to evaluate the potential clinical and economic outcomes of using CYP2C9 genotype data to guide the management of SU regimen in patients initiating glimepiride therapy, and to identify factors affecting the cost-effectiveness of this treatment scheme. The analysis was conducted using a decision tree, considering a 1-year time horizon, and taking as perspective that of the French national health insurance system. With pharmacogenetic-guided therapy, the cost to avoid an episode of severe hypoglycaemia event per 100 000 patients treated was €421 834. Genotyping cost was the most influential factor on the incremental cost-effectiveness ratio. In conclusion, the potential cost of CYP2C9 genotype-guided dosing for glimepiride therapy is relatively high, and associated with modest improvements with respect to the number of hypoglycaemia avoided, as compared with standard dosing. Additional economic studies are required to better specify the usefulness of CYP2C9 genotyping prior to glimepiride regimen initiation.

PMID:33731883 | DOI:10.1038/s41397-021-00232-w

Pharmacogenomics J. 2021 Mar 17. doi: 10.1038/s41397-021-00217-9. Online ahead of print.

ABSTRACT

Certain breast and ovarian cancers are characterised by high levels of chromosomal instability. We established a suite of eleven SNP array-based signatures of various forms of chromosomal instability. To understand what biological mechanisms might underpin these signatures, we generated and assembled genetic-feature data including allele-specific expression, fusion genes, gene expression, methylation, somatic coding mutations and protein expression. For each signature, we extracted a compendium of significantly associated genetic features using machine learning. We established an association between subchromosomal allelic imbalance-based measures and DNA repair genes. Numerical chromosomal instability and chromothripsis were found to have distinct genetic associations but shared a relationship to mitotic processes, while whole-genome doubling was characterised by TP53 mutation, and high AURKA and GINS1 expression. Furthermore, we identified two genetically distinct forms of tandem duplicator phenotypes. These findings identify potentially novel genomic targets for validation and drug development for specific subsets of breast and ovarian cancer.

PMID:33731882 | DOI:10.1038/s41397-021-00217-9

Pharmacogenomics J. 2021 Mar 17. doi: 10.1038/s41397-021-00229-5. Online ahead of print.

ABSTRACT

Previous research has identified differences in mutation frequency in genes implicated in chemotherapy resistance between mucinous and non-mucinous colorectal cancers (CRC). We hypothesized that outcomes in mucinous and non-mucinous CRC may be influenced by expression of genes responsible for chemotherapy resistance. Gene expression data from primary tumor samples were extracted from The Cancer Genome Atlas PanCancer Atlas. The distribution of clinical, pathological, and gene expression variables was compared between 74 mucinous and 521 non-mucinous CRCs. Predictors of overall survival (OS) were assessed in a multivariate analysis. Kaplan-Meier curves were constructed to compare survival according to gene expression using the log rank test. The median expression of 5-FU-related genes TYMS, TYMP, and DYPD was significantly higher in mucinous CRC compared to non-mucinous CRC (p < 0.001, p = 0.003, p < 0.001, respectively). The median expression of oxaliplatin-related genes ATP7B and SRPK1 was significantly reduced in mucinous versus non-mucinous CRC (p = 0.004, p = 0.007, respectively). At multivariate analysis, age (odds ratio (OR) = 0.96, p < 0.001), node positive disease (OR = 0.49, p = 0.005), and metastatic disease (OR = 0.32, p < 0.001) remained significant negative predictors of OS, while high SRPK1 remained a significant positive predictor of OS (OR = 1.59, p = 0.037). Subgroup analysis of rectal cancers demonstrated high SRPK1 expression was associated with significantly longer OS compared to low SRPK1 expression (p = 0.011). This study highlights that the molecular differences in mucinous CRC and non-mucinous CRC extend to chemotherapy resistance gene expression. SRPK1 gene expression was associated with OS, with a prognostic role identified in rectal cancers.

PMID:33731881 | DOI:10.1038/s41397-021-00229-5

Chin Med. 2021 Mar 17;16(1):28. doi: 10.1186/s13020-021-00436-z.

ABSTRACT

BACKGROUND: Ginsenoside CK (GCK) serves as the potential anti-colorectal cancer (CRC) protopanaxadiol (PPD)-type saponin, which could be mainly bio-converted to yield PPD by gut microbiota. Meanwhile, the anti-CRC effects of GCK could be altered by gut microbiota due to their different diversity in CRC patients. We aimed to investigate the bioconversion variation of GCK mediated by gut microbiota from CRC patients by comparing with healthy subjects.

METHODS: Gut microbiota profiled by 16S rRNA gene sequencing were collected from healthy volunteers and CRC patients. GCK was incubated with gut microbiota in vitro. A LC-MS/MS method was validated to quantify GCK and PPD after incubation at different time points.

RESULTS: The bioconversion of GCK in healthy subjects group was much faster than CRC group, as well as the yield of PPD. Moreover, significant differences of PPD concentration between healthy subjects group and CRC group could be observed at 12 h, 48 h and 72 h check points. According to 16S rRNA sequencing, the profiles of gut microbiota derived from healthy volunteers and CRC patients significantly varied, in which 12 differentially abundant taxon were found, such as Bifidobacterium, Roseburia, Bacteroides and Collinsella. Spearman's correlation analysis showed bacteria enriched in healthy subjects group were positively associated with the biotransformation of GCK, while bacteria enriched in CRC group displayed non correlation character. Among them, Roseburia which could secrete β-glycosidase showed the strongest positive association with the bioconversion of GCK.

CONCLUSIONS: The bioconversion of GCK in healthy subjects was much faster than CRC patients mediated by gut microbiota, which might alter the anti-CRC effects of GCK.

PMID:33731196 | DOI:10.1186/s13020-021-00436-z

Public Health Genomics. 2021 Mar 17:1-11. doi: 10.1159/000513753. Online ahead of print.

ABSTRACT

BACKGROUND AND AIM: Mapping the power, interest, and stance of stakeholders is a cornerstone for genomic medicine implementation. In this study, we aimed at mapping the power/interest of various stakeholders in United Arab Emirates (UAE) and exploring their attitudes toward pressing health genomics aspects. The overarching aim of this study is to facilitate the construction of a road map for the full implementation of genomic medicine and pharmacogenomics in the UAE with potential applicability to many healthcare systems around the world.

METHODS: A qualitative approach using in-depth interview was employed. Heterogeneous stakeholders were identified by experts in the field. The analysis of the data was a hybrid of deductive and inductive approach using NVivo software for coding and analysis.

RESULTS: 13 interviews were conducted. Following mapping the Mendelow's matrix, we categorized the stakeholders in UAE to promoter, latent, defender, and apathetic. Most of the interviewed stakeholders emphasized the clinical demand for genomic medicine in UAE. However, many of them were less inclined to articulate the need for pharmacogenomics at the moment. The majority of stakeholders in UAE were in favor of building infrastructure for better genetic services in the country. Stakeholder from an insurance sector had contradicting stance about the cost-effectiveness of genomic medicine; the majority were concerned with the legal and ethical aspects of genomic medicine and had an opposing stance on direct-to-consumer kits.

CONCLUSIONS: Implementing the Mendelow's model will allow the systematic strategy for implementing genomic medicine in UAE. This can be achieved by engaging the key players (promoters and defenders) as well as engaging and satisfying the latent stakeholder.

PMID:33730737 | DOI:10.1159/000513753

Redox Biol. 2021 Mar 10;41:101938. doi: 10.1016/j.redox.2021.101938. Online ahead of print.

ABSTRACT

COVID-19 incidence and case fatality rates (CFR) differ among ethnicities, stimulating efforts to pinpoint genetic factors that could explain these phenomena. In this regard, the multiallelic apolipoprotein E (APOE) gene has recently been interrogated in the UK biobank cohort, demonstrating associations of the APOE ε4/ε4 genotype with COVID-19 severity and mortality. The frequency of the ε4 allele and thus the distribution of APOE ε4/ε4 genotype may differ among populations. We have assessed APOE genotypes in 1638 Greek individuals, based on haplotypes derived from SNP rs7412 and rs429358 and found reduced frequency of ε4/ε4 compared to the British cohort. Herein we discuss this finding in relation to CFR and hypothesize on the potential mechanisms linking APOE ε4/ε4 to severe COVID-19. We postulate that the metabolic deregulation ensued by APOE4, manifested by elevated cholesterol and oxidized lipoprotein levels, may be central to heightened pneumocyte susceptibility to infection and to exaggerated lung inflammation associated with the ε4/ε4 genotype. We also discuss putative dietary and pharmacological approaches for the prevention and management of COVID-19 in APOE ε4/ε4 individuals.

PMID:33730676 | DOI:10.1016/j.redox.2021.101938

Per Med. 2021 Mar 17. doi: 10.2217/pme-2020-0084. Online ahead of print.

ABSTRACT

Aim: We sought to explore how early adopters use pharmacogenomic (PGx) testing for treating depression and attention-deficit/hyperactivity disorder. Patients & methods: Prescribers of the Informed PGx (Progenity, Inc., Ann Arbor, MI 48108, USA) test completed a phone survey assessing use of PGx testing for different scenarios. We conducted a qualitative thematic text analysis of transcribed audio recordings of open-ended responses (n = 62). Results: PGx testing was used when treating multiple comorbidities or resistant disease, and to ease patients' concerns with future therapy. Use of PGx testing is influenced by insurance coverage, interpretability of results and results turnaround time. Conclusion: Prescribers used PGx tests to modify medications for complex patients with depression, attention-deficit/hyperactivity disorder and other disorders to alleviate concerns related to adverse effects and lack of effectiveness.

PMID:33728996 | DOI:10.2217/pme-2020-0084

Per Med. 2021 Mar 17. doi: 10.2217/pme-2020-0083. Online ahead of print.

ABSTRACT

Aim: We sought to understand how early adopters used pharmacogenomic (PGx) testing for treating depression and attention deficient hyperactivity disorder (ADHD). Patients & methods: We conducted a phone survey with prescribers who had previously ordered an Informed PGx (Progenity, Inc., MI, USA) test. Results: We identified 1037 prescribers in our sampling period. Respondents (n = 64) were predominantly female (61.5%) and in pediatrics (n = 42; 64.6%). PGx testing was used for multiple scenarios (mean 3.3 ± 1.6); the most common was after no response to medication was observed (80%; 51/64). Most respondents state that test results typically reveal an altered metabolizer status. Conclusion: PGx test results ordered by early adopters often reveal altered metabolizers which leads them to change the depression/ADHD medication regimen. Future work should evaluate the clinical utility of PGx testing for depression/ADHD treatment.

PMID:33728966 | DOI:10.2217/pme-2020-0083

Pharmacogenomics. 2021 Mar 17. doi: 10.2217/pgs-2020-0143. Online ahead of print.

ABSTRACT

Oxycodone is a semisynthetic μ- and κ-opioid receptor with agonist with a broad scope of use including postoperative analgesia as well as control of neuropathic and cancer pain. Advantages over other opioids include prolonged duration of action, greater potency than morphine and lack of histamine release or ceiling effect. Individual responses to oxycodone can vary due to genetic differences. This review article aims to summarize the oxycodone literature and provide context on its pharmacogenomics and pharmacokinetics. The evidence for clinical effect of genetic polymorphisms on oxycodone is conflicting. There is stronger evidence linking polymorphic genetic enzymes CYP2D6 and CYP3A with therapeutic outcomes. Further, research is needed to discern all of oxycodone's metabolites and their contribution to the overall analgesic effect.

PMID:33728947 | DOI:10.2217/pgs-2020-0143

Eur Ann Allergy Clin Immunol. 2021 Mar 16. doi: 10.23822/EurAnnACI.1764-1489.193. Online ahead of print.

ABSTRACT

Background. Severe cutaneous adverse reactions (SCAR) are potentially fatal reactions. Genetic predisposition is involved in their pathogenesis related to drugs and ethnicities, however in a mixed population these relationships are still unknown. The aim of this study was to describe phenotypes, suspect drugs and HLA-alleles related to SCAR, identified by a systematized approach in a Brazilian case series. Methods. Patients who were diagnosed with SCAR between March 2011 and July 2019 at our university hospital were included. European Network for Drug Allergy (ENDA) questionnaire was used to collect clinical and laboratory data and algorithms for assessment of drug causality were applied. Socio-demographic variables included age, gender and skin color/ethnicity. Drug patch tests (DPT) and HLA-A, -B, -DRB1 typing were carried out. Results. A total of 74 patients were included: 36 (48.64%) with SJS/TEN, 32 (43.24%) DRESS/DIHS, 3 (4.05%) AGEP, 2 (2.70%) overlap(DRESS/SJS and DRESS/AGEP) and 1 (1.35%) GBFDE. The median age was31.5 years (IQR = 14-52.25), most were female (n = 44/59.46%) and brown (n = 38/51.35%). Anticonvulsants (n = 32/43.24%) were the largest group involved and antibiotics (n = 26/35.13%) were the second most common. Two patients with DRESS died during the acute phase. Positive DPT were shown only in anticonvulsant associated DRESS. HLA related to abacavir, allopurinol and carbamazepine were identified. Conclusions. A systematized approach allowed the phenotypic characterization of SCAR. The HLA-A*31:01, B*57:01 and B*58:01 alleles were identified, reinforcing the causality in SCAR by CBZ, ABC and ALLO in the Brazilian population.

PMID:33728835 | DOI:10.23822/EurAnnACI.1764-1489.193

Clin Epidemiol. 2021 Mar 8;13:183-195. doi: 10.2147/CLEP.S289031. eCollection 2021.

ABSTRACT

PURPOSE: To assess the association between VKORC1 and CYP2C9 variants and the incidence of adverse drug reactions in warfarin-treated patients in a real-world setting.

MATERIALS AND METHODS: This was a register-based cohort study (PreMed) linking data from Finnish biobanks, national health registries and patient records between January 1st 2007 and June 30th 2018. The inclusion criteria were: 1) ≥18 years of age, 2) CYP2C9 and VKORC1 genotype information available, 3) a diagnosis of a cardiovascular disease, 4) at least one warfarin purchase, 5) regular INR tests. Eligible individuals were divided into two warfarin sensitivity groups; normal responders, and sensitive and highly sensitive responders based on their VKORC1 and CYP2C9 genotypes. The incidences of clinical events were compared between the groups using Cox regression models.

RESULTS: The cohort consisted of 2508 participants (45% women, mean age of 69 years), of whom 65% were categorized as normal responders and 35% sensitive or highly sensitive responders. Compared to normal responders, sensitive and highly sensitive responders had fewer INR tests below 2 (median: 33.3% vs 43.8%, 95% CI: -13.3%, -10.0%) and more above 3 (median: 18.2% vs 6.7%, 95% Cl: 8.3%, 10.8%). The incidence (per 100 patient-years) of bleeding outcomes was 5.4 for normal responders and 5.6 for the sensitive and highly sensitive responder group (HR=1.03, 95% CI: 0.74, 1.44). The incidence of thromboembolic outcomes was 4.9 and 7.8, respectively (HR=1.48, 95% CI: 1.08, 2.03).

CONCLUSION: In a real-world setting, genetically sensitive and highly sensitive responders to warfarin had more high INR tests and required a lower daily dose of warfarin than normal responders. However, the risk for bleeding events was not increased in sensitive and highly sensitive responders. Interestingly, the risk of thromboembolic outcomes was lower in normal responders compared to the sensitive and highly sensitive responders.

TRIAL REGISTRATION: NCT04001166.

PMID:33727862 | PMC:PMC7954279 | DOI:10.2147/CLEP.S289031

Medicine (Baltimore). 2021 Mar 19;100(11):e24545. doi: 10.1097/MD.0000000000024545.

ABSTRACT

The objective of the present study was to assess the allelic variations of Cytochrome P450 (CYP) enzymes Cytochrome P450 2C19 (CYP2C19), Cytochrome P450 2C9 (CYP2C9), and Cytochrome P450 2D6 (CYP2D6) as they play a major role in drug metabolism. The interindividual genetic variabilities of these enzymes can account for different responsiveness as well as concentration fluctuations for a particular drug.During the period of 2017 to 2018 a total of 54 patients have received pharmacogenetic testing at the Department of Genetics and Molecular Medicine at Kaunas Clinics. According to the genotype-metabolic phenotypes of CYP2C19, CYP2D6, CYP2C9 enzymes patients were classified according to the guidelines by Clinical Pharmacogenetics Implementation Consortium (CPIC): normal metabolizers (NMs), intermediate metabolizers (IMs), rapid metabolizers (RMs), ultrarapid metabolizers (UMs), and poor metabolizers (PMs).CYP2C19 enzyme allelic distribution: 18 patients (33.33%) with ∗1/∗1 genotype were NMs; 14 patients (25.93%) with ∗1/∗2; ∗2/∗17 genotypes were classified as IMs; 15 patients (27.78%) possessed ∗1/∗17 genotype and were RMs; 4 patients (7.4%) had ∗17/∗17 genotype with increased enzyme activity compared with RMs, were classified as UMs; 3 patients (5.56%) had ∗2/∗2 genotype and were marked as PMs. CYP2D6 enzyme allelic distribution: 26 patients (48.148%) contained ∗1/∗1,∗2/∗2,∗1/∗2,∗1/∗41,∗2/∗41 genotypes with normal enzymatic function so were accounted as NMs; 21 patients (38.89%) with ∗1/∗5, ∗2/∗4, ∗10/∗41, ∗1/∗4, ∗1/∗3, ∗2/∗5, ∗2/∗4, ∗2/∗6 genotypes were accounted as IMs; 2 patients (3.7%) possessed ∗2XN genotype and were accounted as UMs and 5 patients (9.26%) possessed ∗4/∗5,∗4/∗10,∗4/∗9,∗4/∗41 genotypes and had non-functional enzymatic activity so were accounted as PMs; CYP2C9 enzyme allelic distribution: 44 patients (81.48%) with∗1/∗1 genotype were NMs; 10 patients (18.52%) with ∗1/∗2;∗1/∗3 genotypes were IMs.The results of our study indicate that deviations from the normal enzymatic activity is common amongst Lithuanian people and combinatory genotyping of CYP2D6, CYP2C9, and CYP2C19 has to be promoted as an advanced method because of most commonly prescribed medicines like analgesics, antihypertensive, antidepressants are metabolized by multiple pathways involving enzymes in the CYP450 family.

PMID:33725937 | DOI:10.1097/MD.0000000000024545

Int Arch Occup Environ Health. 2021 Mar 16. doi: 10.1007/s00420-021-01677-z. Online ahead of print.

ABSTRACT

Zoonotic tuberculosis caused by Mycobacterium bovis (M. bovis), a member of Mycobacterium tuberculosis complex (MTBC) has increasingly gathered attention as a public health risk, particularly in developing countries with higher disease prevalence. M. bovis is capable of infecting multiple hosts encompassing a number of domestic animals, in particular cattle as well as a broad range of wildlife reservoirs. Humans are the incidental hosts of M. bovis whereby its transmission to humans is primarily through the consumption of cattle products such as unpasteurized milk or raw meat products that have been contaminated with M. bovis or the transmission could be due to close contact with infected cattle. Also, the transmission could occur through aerosol inhalation of infective droplets or infected body fluids or tissues in the presence of wound from infected animals. The zoonotic risk of M. bovis in humans exemplified by miscellaneous studies across different countries suggested the risk of occupational exposure towards M. bovis infection, especially those animal handlers that have close and unreserved contact with cattle and wildlife populations These animal handlers comprising of livestock farmers, abattoir workers, veterinarians and their assistants, hunters, wildlife workers as well as other animal handlers are at different risk of contracting M. bovis infection, depending on the nature of their jobs and how close is their interaction with infected animals. It is crucial to identify the underlying transmission risk factors and probable transmission pathways involved in the zoonotic transmission of M. bovis from animals to humans for better designation and development of specific preventive measures and guidelines that could reduce the risk of transmission and to protect these different occupational-related/populations at risk. Effective control and disease management of zoonotic tuberculosis caused by M. bovis in humans are also hindered by various challenges and factors involved at animal-human interface. A closer look into factors affecting proper disease control and management of M. bovis are therefore warranted. Hence, in this narrative review, we have gathered a number of different studies to highlight the risk of occupational exposure to M. bovis infection and addressed the limitations and challenges underlying this context. This review also shed lights on various components and approaches in tackling M. bovis infection at animal-human interface.

PMID:33725176 | DOI:10.1007/s00420-021-01677-z

Brain. 2021 Mar 16:awab090. doi: 10.1093/brain/awab090. Online ahead of print.

ABSTRACT

Hemorrhagic transformation is a complication of recombinant tissue-plasminogen activator (rtPA) treatment. The most severe form, parenchymal hematoma, can result in neurological deterioration, disability, and death. Our objective is to identify single nucleotide variations associated with a risk of parenchymal hematoma following thrombolytic therapy in acute ischemic stroke patients. A fixed-effect genome-wide metanalysis was performed combining two-stage Genome Wide Association studies (GWAs) (n = 1,904). The Discovery Stage (3 cohorts) comprised 1,324 ischemic stroke individuals, of whom 5.4% had a parenchymal hematoma. Genetic variants yielding a p-value <1x10-5 were analyzed in the Validation Stage (6 cohorts), formed by 580 ischemic stroke patients with 12.1% hemorrhagic events. All the participants received rtPA; cases were parenchymal hematoma type 1 or 2 as defined by the ECASS criteria. Genome-wide significant findings (p < 5x10-8) were characterized by in-silico functional annotation, gene expression, and DNA regulatory elements. We analyzed 7,989,272 single nucleotide polymorphisms (SNPs) and identified a Genome-wide association locus on chromosome 20 in the Discovery Cohort; functional annotation indicated that the ZBTB46 gene was driving the association for Chrosome 20. The top SNP was rs76484331 in the ZBTB46 gene (p = 2.49x10-8; odds ratio (OR): 11.21; 95% confidence interval (CI): 4.82-26.55). In the Replication Cohort (n = 580), the rs76484331 polymorphism was associated with parenchymal hematoma (p = 0.01), and the overall association after meta-analysis increased (p = 1.61x10-8; OR: 5.84; 95%CI: 3.16-10.76). ZBTB46 codes the Zinc Finger and BTB domain-containing protein 46 that acts as a transcription factor. In-silico studies indicated that ZBTB46 is expressed in brain tissue by neurons and endothelial cells. Moreover, rs76484331 interacts with the promoter sites located at 20q13. In conculsion, we identified single nucleotide variants in the ZBTB46 gene associated with a higher risk of parenchymal hematoma following rtPA treatment.

PMID:33723576 | DOI:10.1093/brain/awab090

CMAJ. 2021 Mar 15;193(11):E371-E377. doi: 10.1503/cmaj.201938.

NO ABSTRACT

PMID:33722828 | DOI:10.1503/cmaj.201938

Res Social Adm Pharm. 2021 Apr;17(4):799-804. doi: 10.1016/j.sapharm.2020.06.013. Epub 2020 Jun 8.

ABSTRACT

Administering medication safely and with confidence is important for both the patient and the prescriber. The individualised adjustment of a medicine dose, based solely on clinical outcomes or the change of a prescribed drug, possibly delays positive patient outcomes. This could lead to suboptimal patient management. Additionally, it could also have a negative pharmacoeconomic impact. The application of pharmacogenetics addresses this matter by refining and improving the safety and efficacy of medicines through a genotype-based prediction of responses. It also stratifies clinical trial populations in drug development in order to identify which patient genotypes benefit most from the drug under study. Although this emerging science presents a lot of prospects, it also raises a significant number of ethical questions. The problem with stratifying patient populations is addressed by promoting responsible and accountable scientific and intellectual liberty. This will avoid discrimination towards vulnerable populations. Therefore, there is a need to encourage informed consent and confidentiality, as well as to promote autonomy, justice, and equity by developing worldwide equivalent ethical, legal, and regulatory frameworks.

PMID:33722354 | DOI:10.1016/j.sapharm.2020.06.013

Circ Cardiovasc Interv. 2021 Mar 16:CIRCINTERVENTIONS120009434. doi: 10.1161/CIRCINTERVENTIONS.120.009434. Online ahead of print.

ABSTRACT

BACKGROUND: Guidelines favor ticagrelor or prasugrel over clopidogrel in patients with myocardial infarction. However, the POPular Genetics trial (Patient Outcome After Primary Percutaneous Coronary Intervention [PCI]) showed that in patients with primary PCI, a CYP2C19 genotype-guided strategy was associated with a lower bleeding risk without increasing thrombotic risk, compared with routine ticagrelor/prasugrel treatment. Nevertheless, optimal P2Y12 inhibitor treatment in specific CYP2C19 genetic subgroups is still a subject of debate.

METHODS: A prespecified subanalysis of the POPular Genetics trial was performed, using patients in whom CYP2C19*2, *3, and *17 genotypes was determined. Two different analyses were planned. The first assessed the effect of the CYP2C19*17 allele in clopidogrel-treated patients. The second compared the effect of clopidogrel in noncarriers of a loss-of-function allele with ticagrelor/prasugrel-treated patients, irrespective of CYP2C19 genotype. Main outcomes were a thrombotic outcome (cardiovascular death, myocardial infarction, stent thrombosis, and stroke) and a bleeding outcome (PLATO [Platelet Inhibition and Patient Outcomes] major and minor bleeding) after 12 months.

RESULTS: A total of 2429 patients were used for analyses. In the first analysis, the CYP2C19*17 polymorphism was not found to have a significant influence on thrombotic (adjusted hazard ratio, 0.95 [95% CI, 0.45-2.02]) or bleeding outcomes (adjusted hazard ratio, 0.74 [95% CI, 0.48-1.18]). In the second analysis, clopidogrel was associated with a lower number of bleeding events compared with ticagrelor/prasugrel (9.9% versus 11.7%, adjusted hazard ratio, 0.74 [95% CI, 0.56-0.96]), without a significant increase in thrombotic events (3.4% versus 2.5%, adjusted hazard ratio, 1.14 [95% CI, 0.68-1.90]).

CONCLUSIONS: In patients with primary PCI not carrying a CYP2C19 loss-of-function allele, the use of clopidogrel compared with ticagrelor or prasugrel was associated with lower bleeding rates, without an increase in thrombotic events. No effect on clinical outcomes was found for the CYP2C19*17 polymorphism.

REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01761786. URL: https://www.trialregister.nl/; Unique identifier: NL2872.

PMID:33722066 | DOI:10.1161/CIRCINTERVENTIONS.120.009434

Curr Probl Cardiol. 2021 Feb 15;46(6):100816. doi: 10.1016/j.cpcardiol.2021.100816. Online ahead of print.

ABSTRACT

BACKGROUND: The use of anticoagulant bridging remains controversial. This study was conducted to evaluate our warfarin periprocedural management in Qatar and investigate the associated clinical outcomes with such management.

METHODS: A prospective cohort study was designed to describe the periprocedural clinical practice in warfarin patients in Qatar and to compare clinical safety and efficacy outcomes between anticoagulant bridging and nonbridging.

RESULTS: 103 patients were recruited. Bridging occurred in 82% of the participants. No thromboembolic events were observed, while 39.1% of patients experienced bleeding events during the study period. The incidence of overall bleeding and major bleeding were numerically higher for bridging group compared to nonbridging but did not reach statistical significance ([30.6% vs 22.2%, P = 0.478] and [12.9% vs 5.6%, P = 0.375], respectively).

CONCLUSION: Warfarin interruption and bridging are overwhelmingly used in warfarin-treated patients in Qatar. While bridging was numerically associated with increased bleeding events, there is no statistical difference in reported clinical events between bridging and nonbridging strategies.

PMID:33721568 | DOI:10.1016/j.cpcardiol.2021.100816

Pharmacol Rep. 2021 Mar 15. doi: 10.1007/s43440-021-00241-3. Online ahead of print.

ABSTRACT

BACKGROUND: Statins are potent cholesterol-lowering drugs that prevent cardiovascular events. microRNAs (miRNAs) modulate the expression of genes involved in metabolic pathways and cardiovascular functions post-transcriptionally. This study explored the effects of statins on the expression of miRNAs and their target genes involved in lipid metabolism in HepG2 cells.

METHODS: HepG2 cells were treated with atorvastatin or simvastatin (0.1-10 µM) for 24 h. The expression of 84 miRNAs and nine target genes, selected by in silico studies, was measured by qPCR Array and TaqMan-qPCR, respectively.

RESULTS: Five miRNAs were upregulated (miR-129, miR-143, miR-205, miR-381 and miR-495) and two downregulated (miR-29b and miR-33a) in atorvastatin-treated HepG2 cells. Simvastatin also downregulated miR-33a expression. Both statins upregulated LDLR, HMGCR, LRP1, and ABCG1, and downregulated FDFT1 and ABCB1, whereas only atorvastatin increased SCAP mRNA levels. In silico analysis of miRNA-mRNA interactions revealed a single network with six miRNAs modulating genes involved in lipogenesis and lipid metabolism. The statin-dysregulated miRNAs were predicted to target genes involved in cellular development and differentiation, regulation of metabolic process and expression of genes involved in inflammation, and lipid metabolism disorders contributing to metabolic and liver diseases.

CONCLUSIONS: Atorvastatin-mediated miR-129, miR-143, miR-205, miR-381, and miR-495 upregulation, and miR-29b, and miR-33a downregulation, modulate the expression of target genes involved in lipogenesis and lipid metabolism. Thus, statins may prevent hepatic lipid accumulation and ameliorate dyslipidemia.

PMID:33721286 | DOI:10.1007/s43440-021-00241-3

J Pediatr Gastroenterol Nutr. 2021 Feb 22. doi: 10.1097/MPG.0000000000003082. Online ahead of print.

ABSTRACT

Since the approval of the first proton pump inhibitor (PPI) in 1989, our knowledge regarding this class of medications has further developed. An increasing amount of data now supports the association between cytochrome P450 2C19 (CYP2C19) phenotype and PPI safety and efficacy. This includes pediatric studies such as those published here and in other pediatric journals within the past year. Moreover, the most recent pediatric Helicobacter pylori guidelines stated that using the PPIs that are less dependent on CYP2C19 for inactivation may be preferred for H. pylori eradication among populations that are more likely to have rapid clearance of CYP2C19-metabolized PPIs. Conversely, pantoprazole package insert recommends a dose reduction in known pediatric CYP2C19 poor metabolizers (PMs), citing a 6-fold increase in serum concentrations compared to normal metabolizers (NMs). The purpose of this communication is to introduce a recently published Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C19 and PPI dosing.

PMID:33720093 | DOI:10.1097/MPG.0000000000003082